Cardiopulmonary arrest in infants and children remains a significant cause of morbidity and mortality. The principle factor influencing outcome in survivors of cardiopulmonary arrest is the neurologic sequelae resulting from hypoxic-ischemic encephalopathy, unfortunately, there are no interventions to reverse the cellular consequences of hypoxic-ischemic encephalopathy. A clinically relevant model of pediatric asphyxial cardiac arrest in postnatal day 17 rats has been developed that has the capacity for invasive physiologic monitoring and resuscitation that mimics guidelines used in humans, biochemical and cellular assessment, and acute and long-term functional outcome assessment with the potential for application of rehabilitation strategies. Preliminary data show key gender differences in glutathione metabolism and activation of apoptotic cascades in the injured brains of juvenile rats after asphyxia and neurons in culture, implying that pathways leading to neurodegeneration and ultimate cell death and survival may be different between sexes. This is of paramount importance because in the present day infants and children are treated similarly after cardiopulmonary arrest whether they are boys or girls, and both genders are affected by this clinical entity in similar proportions. To our knowledge the influence of gender in the pathobiology of hypoxic-ischemic encephalopathy after cardiopulmonary arrest prior to sexual maturation has not been thoroughly addressed. Using this in vivo model of asphyxial cardiopulmonary arrest in juvenile rats, coupled with parallel in vitro studies, the hypothesis that global hypoxemia-ischemia/reperfusion initiates gender specific cell death pathways and reversible neurological impairments will be tested. Specific Aims are designed to determine whether neuroprotection can be achieved using novel therapies specifically targeting glutathione depletion and apoptosis, and whether therapeutic efficacy is gender-dependent. Dismal outcomes seen in infants and children after cardiopulmonary arrest and the resultant societal impact warrant rigorous pre-clinical testing in a clinically relevant model. The primary objective of this research proposal is to identify efficacious and gender-specific the clinical trials designed to improve outcome in infants and children after cardiopulmonary arrest and gender-specific, therapeutic strategies, to serve as the foundation for clinical trials designed to improve outcome in infants and children after cardiopulmonary arrest.